The brain is an obligate glucose consumer and is unable to synthesize or store more than a few minutes of glucose for use during hypoglycemia. Normal subjects who experience recurrent hypoglycemia have increased rates of brain glucose uptake during subsequent hypoglycemia and therefore have no need to signal for counterregulatory hormone responses to increase systemic glucose production. This alteration leads to symptomatic unawareness of subnormal glucose concentrations. In patients with type 1 diabetes this adaptation contributes to an increased risk of serious hypoglycemia (seizures, comas, and episodes requiring the assistance of others in order to recover). The precise mechanism by which this adaptation occurs and the time course over which it can be induced have not been elucidated. In concert with low systemic glucose concentrations, cortisol concentrations rise during hypoglycemia and may be involved in inducing an increased brain glucose uptake. Over-insulinization associated with hypoglycemia may also play a role in the development of increased brain glucose uptake and the development of hypoglycemia unawareness. Each of the afore-mentioned issues will be addressed in normal man in experiments planned for the initial years of this proposal. Past experiments at the University of New Mexico have demonstrated that rates of brain oxygen utilization fail to decrease during hypoglycemia despite significant reductions in whole brain glucose uptake. Two possible mechanisms seem tenable: 1) that the amount of glucose metabolized anaerobically decreases and/or 2) alternate fuels like lactate, ketones or glutamate are oxidized instead of glucose. Experiments utilizing uniformly labeled 13C-glucose kinetics and determining the rate of appearance of uniformly labeled 13C-lactate in cortical venous effluent will assess whether or not rates of anaerobic glycolysis decrease during hypoglycemia. Also, since the brain may have the capacity to consume lactate or ketones during hypoglycemia, kinetic modeling utilizing stable isotopes of these potential fuels will be completed to assess their use as alternate fuels. These studies will help define basic brain metabolism pertinent to over 1 million patients with type 1 diabetes. Better metabolic control, the key to the prevention of long-term complications of diabetes, will thus become more achievable.